Genetic analysis of the P13K/Akt pathway in thyroid benign and malignant disease

描述(申请人提供)：甲状腺增生性疾病，从临床上无症状的结节增生到腺瘤性甲状腺肿，包括甲状腺癌，影响了很大一部分美国人口，女性的患病率高于男性。虽然大多数结节是良性的，但大约5%的结节发展为恶性特征，仅凭形态特征很难预测任何特定病变的命运。通过识别与结节生长增加或正在进行的甲状腺去分化相关的途径，我们预测或识别高度流行的结节性甲状腺疾病中的甲状腺癌的能力将大大提高。大量临床资料表明，PI3K/PTEN/AKT通路在甲状腺增生性疾病中起重要作用。该项目广泛的、长期的目标是测试以下假设：PI3K/AKT通路的激活会导致良性的甲状腺过度增殖性疾病，它与雌激素信号相互作用，以确定女性更高的增殖指数和更高的腺瘤发生率，以及它在协同遗传变化发生时促进恶性转化的假设。我们建议通过直接的体内方法在一个基因定义的系统中验证这些假说，具体目标如下：目标1：在体内和体外表征PI3K/PTEN/AKT轴的激活在小鼠甲状腺中诱导的功能和分子变化。目的：探讨雌性突变小鼠循环雌激素促进甲状腺细胞增殖和腺瘤易感性的机制。目的：在体内和体外验证PI3K/AKT激活使甲状腺细胞克服RAS激活引发的抑制反馈信号，从而诱导甲状腺细胞恶性转化的假说。公共卫生相关性：《甲状腺学》的终极挑战是在高度流行的结节性甲状腺疾病中预测甲状腺癌。因此，确定与结节生长增加或正在进行的甲状腺转化相关的途径将是理想的。我们的初步数据表明，在体内，慢性PI3K活性足以诱导甲状腺增生并为肿瘤转化创造肥沃的土壤。因此，我们处于一个独特的位置，能够在体内更好地了解结节性甲状腺疾病的发展及其向甲状腺滤泡性肿瘤发展的机制。

DESCRIPTION (provided by applicant): Thyroid proliferative disorders, ranging from clinically silent nodular hyperplasia to adenomatous goiter, and including thyroid cancer, affect a large part of the United States population, with a higher prevalence in women than in men. Although most nodules are benign, approximately 5% of them develop malignant features, and it is hard to predict the fate of any specific lesion, using only morphological features. Our ability to predict or identify thyroid cancer among the highly prevalent condition of nodular thyroid disease would be greatly improved by the identification of pathways that correlate with increased nodule growth or ongoing thyroid dedifferentiation. Numerous clinical data have recently pointed to the PI3K/PTEN/AKT pathway as a crucial player in thyroid proliferative disorders. The broad, long-term objective of this project is to test the hypotheses that activation of the PI3K/AKT pathway induces a benign thyroid hyperproliferative disorder, that it crosstalks with estrogen signaling to determine a higher proliferation index and increased adenoma incidence in females, and that it facilitates malignant transformation upon development of cooperating genetic alterations. We propose to test these hypotheses through a direct in vivo approach in a genetically defined system, with the following specific aims: Aim 1: To characterize in vivo and ex vivo the functional and molecular alterations induced in the mouse thyroid by the activation of the PI3K/PTEN/AKT axis. Aim 2: To elucidate the mechanisms through which circulating estrogens increase thyrocyte proliferation and adenoma susceptibility in female mutant mice. Aim 3: To test in vivo and ex vivo the hypothesis that PI3K/AKT activation allows thyroid cells to overcome inhibitory feedback signals initiated by Ras activation, thus inducing malignant thyrocyte transformation. PUBLIC HEALTH RELEVANCE: The ultimate challenge in "thyroidology" is the prediction of thyroid cancer among the highly prevalent condition of nodular thyroid disease. Thus it would be ideal to define pathways that correlate with increased nodule growth or ongoing thyroid transformation. Our preliminary data demonstrate that chronic PI3K activity is sufficient, in vivo, to induce thyroid hyperplasia and to create fertile ground for neoplastic transformation. Consequently we are in a unique position to achieve in vivo a better understanding of the mechanisms responsible for the development of nodular thyroid disease and its progression to thyroid follicular neoplasms.